The field of the invention is magnetic resonance imaging (MRI), and particularly, the imaging of tumors in the human brain and other parts of the body.
In the United States, approximately 17,000 new patients are diagnosed each year with a primary intracranial neoplasm. Approximately 60% of these tumors are malignant, and gliomas are the most common type. Although there is a wide variability in life expectancy for patients with the various subtypes of gliomas, their prognosis is generally poor. This is especially true for those with high-grade gliomas, in spite of treatment modalities such as surgery, radiation therapy and chemotherapy. The most aggressive gliomas are those characterized by angiogenesis, a process of new vessel growth essential for the progression of the tumor from low-grade to high-grade. There is also a clear correlation between increased vascularity of the tumor and increased malignancy. Given the vascular nature of these tumors and the lack of success with standard cancer treatments, there is both a great need and hope for therapies that inhibit angiogenesis. Now that several of these agents are entering clinical trials an assessment of their ability to inhibit angiogenesis is crucial to evaluating their clinical potential.
Contrast-enhanced conventional MRI methods have become the imaging standard for the depiction and detection of brain tumors. However, these post-contrast, steady-state methods do not provide reliable information about tumor angiogenesis. The tumor signal enhancement volume that is measured by these prior methods depends on the status of the blood-brain barrier, which is affected by both tumor type and prior treatments for the disease. In addition, a tumor's response to an anti-angiogenic therapy can occur before effects on tumor volume can be detected, or may even occur with increases in tumor volume that result from the evolution of local necroses. Finally, an anti-angiogenic therapy may be judged successful, not necessarily because it results in tumor shrinkage, but because it stabilizes the tumor or returns it to a dormant state. For these reasons, non-invasive methods that can more specifically monitor vessel growth and regression in tumors are needed for the evaluation of anti-angiogenic therapies.
Over the past decade, contrast agent based MRI methods, both relaxivity (T1) and susceptibility (T2, T2*)-weighted methods, have demonstrated the potential to measure many characteristics of tumor hemodynamics. The T1 methods, commonly termed dynamic contrast enhanced (DCE) MRI, have been widely used for estimating the plasma-tissue contrast agent transfer constant, Ktrans, and the extravascular extracellular space (EES). Of these, perhaps the most reliable parameter is Ktrans, which has been shown to change during angiogenic therapy.
The T2 or T2* methods typically referred to as dynamic susceptibility contrast (DSC) MRI have been commonly used to measure tumor cerebral blood volume (CBV) and more recently the cerebral blood flow (CBF), and mean transit time (MTT). DSC derived tumor blood volume data have demonstrated a correlation with tumor grade. The MTT can be used as an indicator of perfusion efficiency and has been shown to be very heterogeneous in rat brain tumor models. Additionally, intravoxel transit time and flow distributions can be computed using DSC methods. These distributions are markers of flow heterogeneity and are useful in the evaluation of antiangiogenic therapies. They have shown great promise in predicting the final infarct size following acute stroke.
DSC methods rely on the compartmentalization of the contrast agent such that a susceptibility gradient can be induced between the contrast-containing compartment, which is typically the vasculature, and the extravascular space. A potential difficulty with DSC MRI methods to study tumors results from the fact that currently only small molecular weight Gadolinium (Gd) agents are available for clinical use. In normal brain tissue, for which the blood-brain-barrier (BBB) is intact, the passage of a bolus of a Gd agent through the tissue induces a susceptibility gradient that results in a signal reduction. However, when there is a disruption of the BBB, as is frequently the case with brain tumors, contrast agent leaks out of the vasculature into the tissue resulting in enhanced T1 relaxation effects. Signal increases that result from shortening T1 competes with the susceptibility-induced signal decreases. As expected, contrast agent leakage can lead to an underestimation of tumor blood volume and flow. In tissues outside of the brain, where no blood brain barrier exists, the Gd contrast agents always leak out of the vascular space. Thus, DSC methods have up until now been somewhat limited in their use outside of the brain.
Numerous techniques have been proposed to eliminate T1 leakage effects including dual echo pulse sequences and model-based permeability compensation methods. The model-based leakage correction methods require no changes in pulse sequence design so that clinically available imaging sequences can be used to measure the dynamic signal changes following contrast administration.
A model-based correction approach is described in U.S. Pat. No. 6,807,441 to correct GE and SE CBV maps for contrast agent leakage. The corrected CBV demonstrated good success in the preliminary evaluation of brain tumors. In particular in a group of 15 patients, it was demonstrated that only when the leakage correction was applied did a statistically significant correlation result between tumor CBV and grade. However, this approach is limited to the calculation of CBV. In order to eliminate leakage effects on other tumor hemodynamic parameters, such as CBF (cerebral blood flow) and MTT (mean transit time), the original MR signal time course must also be corrected for leakage effects prior to their determination.